Project One will examine the hypothesis that estrogen receptor (ER) and epidermal growth factor receptor[unreadable] (EGFR) activate proliferative signaling pathways in non-small cell lung cancer (NSCLC), and that these[unreadable] signaling pathways overlap and interact. Based on results obtained in the first SPORE grant period, we[unreadable] hypothesize that ER expression and signaling have functional significance in NSCLC and that co-inhibition of[unreadable] ER and EGFR may show greater anti-tumor activity in NSCLC than inhibition of either pathway alone. Data[unreadable] obtained in the first SPORE grant period suggest that there may be some sex differences in the ER pathway[unreadable] in lung cancer, but that the ER pathway is also active in males. We will carry out this translational research[unreadable] project targeting the ER and the EGFR in four specific aims: (1) Determine signaling molecules involved in[unreadable] ER-EGFR pathway interactions in NSCLC cell lines; (2) Examine effectiveness of joint inhibition of the EREGFR[unreadable] pathways on tumor growth compared to single therapy in NSCLC, using clinically relevant agents; (3)[unreadable] Determine if aromatase, the enzyme that synthesizes estrogen, is present and functional in normal and[unreadable] malignant lung cells and if an aromatase inhibitor has anti-tumor activity; and (4) Analyze ER and EGFR[unreadable] pathway status in tissues obtained from NSCLC patients on clinical trials using combination therapy. Results[unreadable] from these aims will demonstrate how the ER and EGFR signaling pathways interact and to what extent[unreadable] ligand-dependent and ligand-independent ER signaling play a role in NSCLC proliferation. Results will also[unreadable] determine whether inhibition of estrogen synthesis is a potentially effective therapeutic strategy for NSCLC.[unreadable] Results will further demonstrate how responses to combined ER and EGFR targeting in a clinical trial are[unreadable] related to ER and EGFR signaling pathways in patients' tumors and whether combined therapy gives[unreadable] superior clinical responses compared to targeting EGFR alone. We will also determine to what extent EGFR[unreadable] with mutation in the tyrosine kinase domain differs from wild type EGFR in the integration of the ER and[unreadable] EGFR pathways. Completion of these aims will provide a new paradigm for treatments targeting the ER in[unreadable] NSCLC that could be applied to both men and women with this disease.